Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110α inhibitors

Abstract 3-{1-[(4-Fluorophenyl)sulfonyl]-1 H -pyrazol-3-yl}-2-methylimidazo[1,2- a ]pyridine, 2a , was discovered in our chemical library as a novel p110α inhibitor with an IC 50 of 0.67 μM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110α inhibitory activity by more than 300-fold ( 2g : IC 50  = 0.0018 μM). Further structural modification of 2g afforded thiazole derivative 12 , which has potent p110α inhibitory activity (IC 50 of 0.0028 μM) and is highly selective for p110α over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC 50 values of 0.14 μM and 0.21 μM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25 mg/kg. These results suggest that selective p110α inhibitors may have potential as cancer therapeutic agents.